title: HuR is a post-transcriptional regulator of core metabolic enzymes in pancreatic cancer.
abstract: Cancer cell metabolism differs from normal cells, yet the regulatory mechanisms responsible for these differences are incompletely understood, particularly in response to acute changes in the tumor microenvironment. HuR, an RNA-binding protein, acts under acute stress to regulate core signaling pathways in cancer through post-transcriptional regulation of mRNA targets. We demonstrate that HuR regulates the metabolic phenotype in pancreatic cancer cells and is critical for survival under acute glucose deprivation. Using three pancreatic cancer cell line models, HuR-proficient cells demonstrated superior survival under glucose deprivation when compared with isogenic cells with siRNA-silencing of HuR expression (HuR-deficient cells). We found that HuR-proficient cells utilized less glucose, but produced greater lactate, as compared with HuR-deficient cells. Acute glucose deprivation was found to act as a potent stimulus for HuR translocation from the nucleus to the cytoplasm, where HuR stabilizes its mRNA targets. We performed a gene expression array on ribonucleoprotein-immunoprecipitated mRNAs bound to HuR and identified 11 novel HuR target transcripts that encode enzymes central to glucose metabolism. Three (GPI, PRPS2 and IDH1) were selected for validation studies, and confirmed as bona fide HuR targets. These findings establish HuR as a critical regulator of pancreatic cancer cell metabolism and survival under acute glucose deprivation. Further explorations into HuR's role in cancer cell metabolism should uncover novel therapeutic targets that are critical for cancer cell survival in a metabolically compromised tumor microenvironment.
authors.affiliation: Department of Surgery; Jefferson Pancreas, Biliary and Related Cancer Center; Philadelphia, PA USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Burkhart
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Pineda
authors.forename: Saswati N
authors.initials: SN
authors.lastname: Chand
authors.forename: Carmella
authors.initials: C
authors.lastname: Romeo
authors.forename: Eric R
authors.initials: ER
authors.lastname: Londin
authors.forename: Edward D
authors.initials: ED
authors.lastname: Karoly
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Cozzitorto
authors.forename: Isidore
authors.initials: I
authors.lastname: Rigoutsos
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Yeo
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Brody
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Winter
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D005956:Glucose-6-Phosphate Isomerase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism*; D015203:Reproducibility of Results; D013312:Stress, Physiological; D059016:Tumor Microenvironment
chemical_list: D016207:Cytokines; D051959:ELAV Proteins; D012333:RNA, Messenger; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C554959:GPI protein, human; D005956:Glucose-6-Phosphate Isomerase; D005947:Glucose
keywords: HuR; cancer metabolism; pancreatic cancer; post-transcriptional gene regulation